The present invention relates generally to pharmaceutical compounds and methods for their use to cause sedative and analgesic effects in animals and humans. More specifically, the invention relates to the use of gamma-pyrones in pharmaceutically acceptable forms for the treatment of various neurotic disorders. For the purposes of this description, the term “neurotic disorder” includes among others such conditions as anxiety, pain, insomnia, depression, neurosis as well as pain and other symptoms associated with treatment of chemical and drug abuse patients. All of these conditions involve the neurons of the central nervous system.
Sedative compounds known in the art are a chemically varied group of compositions of natural and synthetic origin that predominantly have a tranquilizing effect on the central nervous system. Different sedatives produce different physiological effects. Understanding of these effects is helpful in selectively treating various disorders. This mechanism of action is not always entirely clear but it is believed that sedative drugs in general are intended to cause selective suppression of subcortical (limbus) and cortical brain structures, which regulate emotions.
The mildest examples of sedative drugs include extracts of motherwort, passiflora, valerian root (Tinctura Valeriana), bromides of caustic metals (Kalium bromatum, Natrium bromatum). These drugs typically cause only a light tranquilizing effect on the subject. Stronger tranquilizers are used to lower a patient's anxiety. These are synthetic medicinal preparations, examples of which include derivatives of benzodiazepin (diazepam), diphenyl methane benactyzine), propanediol (mepropan) and trioxazin.
Hypnotic compounds (Phenobarbital for example) in small doses are also used as sedative drugs along with various neuroleptic agents (aminazine, tisercin) and some other compounds. Examples of such additional compounds include Bekhterev's mixture (sodium bromide, lychnis infusion, codeine phosphate), Corvalolum (ethyl ether of α-bromine isovaleric acid, monosodium salt of Phenobarbital, mint oil, ethyl alcohol, water), and Validol (menthol solution in menthyl valerate).
An example of a general sedative compound is shown in the U.S. Pat. No. 5,506,268 by Balandrin describing the use of isovaleramide as a mild anxiolytic and sedative agent.
The side effects of these medicinal preparations are a reduced ability to concentrate, drowsiness, and lower mental and physical effectiveness. In addition, patients often become dependent on a sedative in the course of treatment, reducing the desired effect, and a replacement sedative is needed to maintain the desired effect.
The need therefore exists for new sedative compounds that do not cause these side effects or drug dependency.
Pharmaceutical compounds used in treating patients with chemical and drug abuse define an important sub-category in the general area of sedative drugs. It is common knowledge that there are many individuals who become addicted to certain types of drugs taken either for medical reasons or for “recreational”, non-medical use. Addiction, as has been defined by the Drug Addiction Committee of the National Research Council, is a state of periodic or chronic intoxication detrimental to the individual and produced by the repeated administration of a drug. Thus, an “addictive drug” as used herein is one that is initially used for any one of a number of purposes, e.g., for the relief of physical or psychic pain, and which if used consistently leads to dependency on the part of the individual taking the drug. The addicted individual develops a continuing craving for the drug and experiences withdrawal symptoms if an attempt is made to discontinue drug use. The terms “withdrawal syndrome” and “abstinence syndrome” are used to mean the same patient's condition for the purposes of this description.
Various pharmacological approaches for treating drug dependence have been tried. These approaches have typically involved attempts at treating the craving for the abused drug or alleviating the symptoms of withdrawal. The following references relate to some known methods and compositions for treating drug addiction and/or symptoms of withdrawal from drug dependency. U.S. Pat. No. 4,786,653 by Golwyn relates to the administration of phenelzine or an equivalent phenylalkylhydrazine, substances that are physiologically incompatible with addictive drugs such as amphetamines and cocaine. U.S. Pat. Nos. 1,796,977 and 1,782,111 describe the preparation of disulfiram (“Antabuse”), an alcohol deterrent. U.S. Pat. No. 4,696,818 by Kim relates to a method for alleviating symptoms associated with a variety of drugs, the method comprising administering an herbal composition to the drug dependent individual. U.S. Pat. No. 3,706,831 by Plotnikoff also describes a method for treating addiction to any one of a number of different types of drugs, which method involves administering to the addict a composition containing 2-imino-5-phenyl-4-oxazolidinone. U.S. Pat. Nos. 4,117,161 and 4,124,715 by Pozuelo disclose methods and compositions for treating withdrawal from narcotics and amphetamines which involve administration of alphamethyl-para-tyrosine or fusaric acid to the affected individual.
Treatment of nicotine withdrawal is described in the U.S. Pat. No. 4,325,952 by Baiocchi et al. and involves the use of a piperazine compound to treat the symptoms associated with withdrawal from nicotine. U.S. Pat. No. 4,788,189 by Glazer involves treatment of nicotine withdrawal by administration of clonidine in conjunction with a tricyclic antidepressant drug. U.S. Pat. No. 4,276,890 by Fichera describes a composition for alleviating symptoms of nicotine withdrawal by administering to the affected individual a composition containing a gamma-pyrone such as maltol or ethyl maltol.
Opioids and their numerous forms including opium, codeine, morphine, heroin etc. as well as its alkaloids and synthetic substitutes constitute a large segment of narcotics in general. Its use has become more widespread recently. The primary method of treatment for opium dependence is the discontinuation of narcotics and minimization of the abstinence syndrome. The only officially permitted method of discontinuation of narcotics involves the replacement from opioid receptors and the substitution of one of three possible ligands: 1. Antagonists of opioid receptors such as naltrexone, naloxone, nalmephine, and antaxone; 2. Agonists/antagonists such as pentazocine, butorphanol, nalbuphine, and buprenorphine aimed to activate receptors of a particular subtype such as kappa, while blocking receptors of another subtype such as mu; and 3. Agonists such as methadone and others that are better controlled and have a lower affinity to receptors, this method is called substitution therapy.
Each of these approaches has its own disadvantages. In the case of antagonists, there is no relief from the pain and other symptoms of withdrawal syndrome. The most severe, long-lasting manifestations of withdrawal syndrome cannot be eliminated either by initial general narcosis or with the assistance of anesthetics, tranquilizers, neuroleptics or antidepressants. These substances have numerous side effects while the incidence of relapse is rather high. With the use of agonists, the withdrawal syndrome is less pronounced; however, a dependence often develops on the medication that is also, in fact, a narcotic, although with a lower affinity to opioid receptors than, for instance, morphine or heroin. Besides, the duration of such substitution therapy is rather long, up to 3–6 months. Due to their psychological instability, drug addicts often “change their mind” and refuse treatment.
Therefore, a very substantial need in the art exists for a therapeutic method of treating drug abuse such that a drug-addicted individual is readily able to discontinue use of an abused drug without encountering the above-mentioned problems and withdrawal symptoms.